Strategies for making vaccines efficacious in the elderly

Transcription

1 Strategies for making vaccines efficacious in the elderly Rino Rappuoli Ageing and Immunity Siena April 22 nd 2012

2 Ageing is good Ageing is most often framed in negative terms. Questioning whether health services, welfare provision, and economic growth are suistanainable. We argue that, instead of being portrayed as a problem, increased human longevity should be a cause of celebration Cover page, The Lancet, April 7-13

3 people live longer

4 Life Expectancy is Growing Beyond Prediction Society is Aging We Need a New Model for Health Care Which factors influenced this change? Life expectancy in the longest living countries. Nature 451, , 2008

5 Crimmins et al. Attribute the Increase of Life Expectancy to the Conquest of Infectious Diseases Reduced infant mortality Less Infectious Diseases Increased Life Expectancy Less inflammation Reduced Mortality in the Elderly

6 More recently, Reductions in Cardiovascular and Infant Mortality are the Key Factors Driving Increased Life Expectancy in the U.S. Life expectancy at birth in years >50% hereof through better medical care of low birth weight infants >50% hereof through improvements in medical care, e.g.,statins, antihyperintensives, aspirin Life expectancy at birth: 1960 Increased life expectancy due to reduced cardiovascular mortality reduced infant death reduction in rate of death due to accident, suicide, homicide reduction in rate of death due to pneumonia, influenza reduction in rate of death due to cancer other causes; e.g., HIV, obesity, others Life expectancy at birth: 2000 Source: Cutler - DM et.,al., NEJM 335;9

7 HIV in Africa Is the Tragic Example of the Impact of Infectious Diseases On Life Expectancy Source: World Bank World Development Indicators, 2004

8 Vaccines were developed for a jounger society Can vaccines help also the 21 st century society?

9 There is a lot of excitement about vaccines The Decade of Vaccines Lancet volume dedicated to vaccines

10 Nature special issue on vaccines

11 During the last 30 years, several new technologies made possible vaccines that were previously impossible Rappuoli et al (2011). Nature Reviews Immunology Isolate Inactivate Inject the causative organism

12 Vaccines will help to address the new the major health challenges of the 21 st century 1 21 st century society, ageing society 2 Emerging infections 3 Poverty

13 Vaccines for every age

14 Vaccines for poverty, emerging infections and special populations

15 During the last 30 years, several new technologies made possible vaccines that were previously impossible Conjugate vaccines

16 Glyco-conjugation improves the immunogenicity of polysaccharides Conjugate vaccines have been instrumental for infant vaccination Recently conjugates have shown benefit against pneumococcus also in the elderly

17 Mechanism of action of conjugate vaccines the dogma 17 Presentation Title Presenter Name Date Subject Business Use Only

18 a new mechanism of action of conjugate vaccines Avci... and Kasper ; Nat. Med Presentation Title Presenter Name Date Subject Business Use Only

19 During the last 30 years, several new technologies made possible vaccines that were previously impossible Reverse Vaccinology

20 Reverse Vaccinology Allowed the Identification of Novel MenB Antigens Based on the genome sequence of MC58, 600 ORFs that potentially encoded novel surface exposed or exported proteins were identified ~350 proteins successfully expressed in E.coli, purified, and used to immunize mice IHT-C 2,200,000 2,100,000 2,000,000 1,900,000 1,800,000 1,700, , ,000 IHT-A 300, , , ,000 IHT-B expression and purification purified proteins 1,600, ,000 1,500,000 1,400,000 1,300,000 1,200, , ,000 1,000,000 1,100,000 immunizations fhbp variant 1 NadA NHBA Testing for bactericidal activity Pizza M. et al. Science 2000

21 Reverse vaccinology allowed us to target many pathogens that were difficult or impossible before Including SUPERBUGS Group B Streptococcus Group A Streptococcus Pneumococcus Chlamydia trachomatis and Pneumoniae Tuberculosis Malaria Gonococcus Porphyromonas gingivalis Yersinia pestis

22 Staphylococcus, 4 antigens combo gives the best protection in the mouse lethality model Survival (%) at different time ponits (days) Survival (%) D-0 D-1 D-2 D-3 D-4 D-5 D-6 D-7 D-8 D-9 D-10 D-11 D-12 D13 D14 Time after challenge (Days) Combo 4 Combo 2 IsdB alum

23 SA-combo reduces abscess formation caused by different strains SA-combo reduces CFU counts and abscess area Newman USA100 CC-30 USA300 Newman Ctr+ Combo Alum Ctr+ Combo Alum Ctr+ Combo Alum Ctr+ Combo Alum P = Newman combo alum

24 Antibiotic resistant E. Coli outbreak Germany June Presentation Title Presenter Name Date Subject Business Use Only

25 25 Presentation Title Presenter Name Date Subject Business Use Only

26 Genome sequence told us that there is no genetic segregation between intestinal and extraintestinal E. coli they share common antigens

27 27 Presentation Title Presenter Name Date Subject Business Use Only

28 3385 induces protection in a mouse sepsis model by active and passive immunization Protection Passive: IV- 100µl rabbit serum IP infection 24h later Bacteremia Moriel et al PNAS. 107(20):9072

29 3385 protection against APEC O strain Passive immunization in a chicken model of sepsis 3385 gene is present and conserved in avian APEC strains, which belong to the ExPEC group and are the main cause of colibacillosis in poultry Antibodies to 3385 protect in passive immunization in a chicken model of sepsis Three day old chicks (Bar-On) Challenge i.p.: 5x10 6 E. coli, in two injections of 0.2 ml each, 3 hrs apart Antibodies anti-3385: 0.15 ml applied s.c. (neck) 20 min after the first injection Study in collaboration with Dr. Ron, Tel Aviv University

30 3385 induces protection in a UTI mouse model Day 0 Day 7 Day 14 Day 21 Day 28 Primary dose Intranasal immunization cholera toxin (ratio 1:10) Boost Boost Challenge 100µg 25µg 25µg 10 8 cfu transurethrally Sacrifice (culture urine, bladder, kidney, spleen) Log 10 CFU/g tissue or /ml urine P= E. coli 536 challenge P= P= P= CBA/J murine model in collaboration with Dr. Mobley, University of Michigan Urine Bladder Kidney Spleen Statistically significant CFU reduction in kidneys and spleen was observed immunizing intranasally with CT as mucosal adjuvant against transurethral challenge with UPEC strain 536

31 During the last 30 years, several new technologies made possible vaccines that were previously impossible Structural Vaccinology

32 Structural Vaccinology engineering a stable F protein for RSV

33 During the last 30 years, several new technologies made possible vaccines that were previously impossible Adjuvants

34 old old + MF59 young The MF59 adjuvant makes the old immune system to behave like a young one!!!!

35 MF59: An established adjuvant in a European-licensed seasonal trivalent vaccine Oil-in-water emulsion adjuvant licensed for use in seasonal influenza vaccine FLUAD * since 1997 More than 100 million commercial doses distributed Adjuvanted vaccine provides heterologous responses to drifted strains >120 Clinical studies, >200,000 subjects No safety signals in either pharmacovigilance database or metaanalysis of clinical trial database with 6 month subject follow-up (filed with CBER) 160nm oil MF59 adjuvant emulsion Antigens SPAN 85 TWEEN 80 Pediatric studies and efficacy trial in 3,000 subjects *FLUAD is a registered trademark of Novartis. FLUAD is not licensed in the Unites States. FLUAD is recommended for active prophylaxis of influenza in the elderly

36 Live study To estimate the risk of hospitalization for influenza-related disease in older adults ( 65 years of age) vaccinated with MF59-adjuvanted influenza vaccine (FLUAD ) compared with non-adjuvanted influenza vaccine Odds ratio (± 95% CI) Broad Intermediate Narrow Risk window For the narrow window, vaccination with FLUAD reduces hospitalizations by an estimated 23% compared with non-adjuvanted vaccine

37 Adjuvants for emerging infections From June to December H1N1 vaccines were: Developed Tested in clinical trials Licensed 180 million doses produced

38 Pediatric Fluad Efficacy Study (n=4707) Efficacy was robust, observed early, and persisted Fluad Pediatric Vaccine efficacy vs. non-influenza control Fluad TIV Vaccine also showed satisfactory safety profile: Increased local reactogenicity No increase in serious adverse experiences vs. control Days post-second dose Vesikari T, et al. NEJM. In press.

39 During the last 30 years, several new technologies made possible vaccines that were previously impossible Alzheimer

40 Vaccination against Alzheimer s disease (mouse) 25 µg CAD106, subcutaneously Age of mice (months) Cortex Control -VLP) (Qβ) End of Experiment CAD106 (Qβ-Aβ1-6) Hippocampus Thalamus Caudate putamen Plaque area (%), Cortex Cortical plaque area ** Brain Aβ42 content 0 PBS Qβ CAD106A Courtesy of A. Graf and the AD Team, Novartis 40 Adjuvants G. Del Giudice Siena, 23 September 2009 Business Use Only Amyloid plaque area ~80 % lower than in control mice

41 During the last 30 years, several new technologies made possible vaccines that were previously impossible New technologies have greatly increased our ability to make vaccines Many scientific gaps are still a major obstacle to develop next generation vaccines Expecially for the elderly that are usually primed to vaccine antigens and have an ageing immune system

42 Maurice Hillemann One man, nine vaccines, that practically every child gets

43

44

45 During the last 30 years, several new technologies made possible vaccines that were previously impossible ADITEC role is to develop the next generation technologies

46 ADITEC STRATEGY

47 14 ADITEC CLINICAL STUDIES ADJUVANTS/ VECTORS NOVEL IMMUNIZATIO N TECHNOLOGI ES PRIME-BOOST ROUTES HOST FACTORS HUMAN IMMUNOLOGY PCS Phase I/2a Phase I Phase 2a Phase I PCS Phase IV Phase IV PCS Phase I/2 Phase II Phase II Phase IV Phase V Licensed vaccines with matched antigens but discordant adjuvant (hepatitis B, influenza, or HPV) Alumnium salts, MF59, TLR agonists, or a mixture of them (Influenza, Men B) New adjuvant developed by ADITEC Novel recombinant BCG Biomics of immune response Trial 1: Shigella sonnei outer membrane particles Trial 2: candidate developed by ADITEC Trial 3: candidate developed by ADITEC Flumist intranasal prime followed by parenteral influenza boost (and reverse) Flumist sub-lingual versus intranasal Dukoral sub-lingual versus oral TBE intramuscolar (tageted lymphnode immunization) Licensed oral salmonella vaccine vs new IM and challenge Young children influenza Elderly avian influenza + ICI31 or MF59 adjvants Licensed HBV in elderly and young Influenza in infants and elderly

48 IMMUNIZATION TECHNOLOGIES ANTIGENS ADJUVANTS/ NON-LIVING DELIVERY SYSTEMS LIVE DELIVERY SYSTEMS KLK ODN1a INFLUENZA IC31 MF59 HA Salmonella Adenovirus GLA-SE CAF Ag85 TB ESAT6 Rv2660 BCG Lentivirus H56 CTB-CpG Virosomes Other model antigen PLA nanoparticles Streptococcus gordonii Arenavirus

49 A new model for advancing vaccine science and development